Myocardial overexpression of adenine nucleotide translocase 1 ameliorates diabetic cardiomyopathy in mice.
Mitochondrial dysfunction is implicated in the pathogenesis of diabetic cardiomyopathy, a common complication of diabetes. Adenosine nucleotide translocase (ANT) translocates ADP/ATP across the inner mitochondrial membrane. Our study aimed to test the hypothesis that overexpression of ANT1 in cardiomyocytes has cardioprotective effects in diabetic cardiomyopathy induced by streptozotocin (STZ). Mice specifically overexpressing murine ANT1 in the heart were generated using alpha-myosin heavy chain promoter. Expression of ANT1 mRNA and protein in hearts was characterized by real-time polymerase chain reaction and Western blot analysis. Five- to 6-month-old male transgenic mice and their age-matched wild-type littermates were subjected to type 1 diabetes induced by STZ. Six weeks later, haemodynamic measurement was performed to assess cardiac function. Ventricular mRNA expression of atrial natriuretic peptide, a molecular marker of heart failure, was characterized by RNase-protection assay. Both ANT1 mRNA and ANT1 protein were specifically overexpressed in the heart of transgenic mice. Heart weight was decreased and cardiac function was dramatically impaired in wild-type mice 6 weeks after induction of diabetes, but ANT1 overexpression prevented these significant changes. The mRNA expression level of atrial natriuretic peptide confirmed the haemodynamic findings, being upregulated in wild-type mice receiving STZ, but showing no statistical differences in ANT1 transgenic mice. Cardiomyocyte-restricted overexpression of ANT1 prevents the development of diabetic cardiomyopathy; therefore, accelerated ADP/ATP exchange could be a new promising target to treat diabetic cardiomyopathy.
Wang
Yong
Y
Department of Cardiology, Charité-Universitätsmedizin Berlin, Germany.
Ebermann
Linda
L
Sterner-Kock
Anja
A
Wika
Sylwia
S
Schultheiss
Heinz-Peter
HP
Dörner
Andrea
A
Walther
Thomas
T
D033741:Adenine Nucleotide Translocator 1 / Q000235:genetics / Q000378:metabolism*; D000244:Adenosine Diphosphate / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D009202:Cardiomyopathies / Q000378:metabolism / Q000517:prevention & control*; D048909:Diabetes Complications / Q000378:metabolism / Q000517:prevention & control*; D003921:Diabetes Mellitus, Experimental / Q000150:complications; D003922:Diabetes Mellitus, Type 1 / Q000150:complications; D004195:Disease Models, Animal; D006943:Hyperglycemia / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D013311:Streptozocin
D033741:Adenine Nucleotide Translocator 1; D012333:RNA, Messenger; D013311:Streptozocin; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate